Hedgehog signaling via its ligand DHH acts as cell fate determinant during skeletal muscle regeneration

Abstract

Failed tissue regeneration often results in fatty fibrosis, the replacement of healthy cells with fibrotic scar and fat tissue. However, the causative signals remain largely unknown. Here, we describe how the Hedgehog (Hh) signaling pathway controls the fate of fibro/adipogenic progenitors (FAPs), the cellular origin of fatty fibrosis. Using conditional mutagenesis and pharmacological Hh modulators, we identify DHH as the main ligand through which Hh restricts intramuscular fat (IMAT) formation and promotes muscle regeneration. In contrast, conditionally activating Hh specifically in FAPs skews them from an adipogenic towards a fibrogenic fate resulting in massive fibrotic scar tissue. Surprisingly, FAP-specific Hh activation also impairs myoblast differentiation leading to muscle regeneration defects. Together, our data reveal novel post-developmental functions of Hh signaling in balancing tissue regeneration and fatty fibrosis. Moreover, they provide the exciting possibility that mis-regulation of the Hh pathway with age and disease could be a major driver of pathological IMAT formation, thereby representing an attractive therapeutic target.